Need for multi-scale systems to identify spindle orientation regulators relevant to tissue disorganization in solid cancers

INTRODUCTION During cell division, the mitotic spindle captures chromosomes and segregates them into two equal sets. The orientation and position of the mitotic spindle is important because the spindle equator becomes the plane of cell division. For instance, in a columnar cell with apical and basal polarity, if the spindle pole-to-pole axis orients along the cell’s long axis, the cell will divide along its short-axis; however, if the spindle axis orients along the cell’s short axis, the cell will divide along its long-axis (Figure 1A). Similarly when the spindle is off-centered (mis-positioned), it results in asymmetric cell sizes in the two daughter cells, which is often used to control tissue organization (Figure 1B). Thus, errors in the orientation and positioning of the mitotic spindle can cause incorrect plane of cell division leading to incorrect cell size, content and neighborhood of daughter cells (Figures 1A,B). A human body experiences over a trillion divisions and through age errors in cell division can accumulate; errors in spindle orientation can contribute to tissue disorganization, a hallmark of several age-related conditions and also, carcinogenesis. However, mutations in classical cortical force generators that rotate the spindle to the correct orientation have not been shown to promote carcinogenesis. In contrast, several proteins known to play a role in cancer initiation and progression are being newly identified as regulators of spindle positioning and orientation. In this opinion article, we briefly discuss the surprising lack of direct evidence for classical spindle rotation regulators in oncogenesis and present examples of oncogenic pathway components that influence spindle orientation.We conclude with the need for new strategies to uncover the contribution of spindle orientation defects to tissue disorganization commonly found in cancers and also ageing disorders.